tbuckley/cabot-search huggingface dataset:
Autoantibodies as potential biomarkers of immune-related adverse events in patients with advanced cutaneous melanoma treated with immune checkpoint inhibitors.
Authors: Aesha Gandhi, John Taylor, Michael Morici, Anna Reid, Tarek Meniawy, Muhammad Adnan Khattak, Elin Gray, Michael Millward, Pauline Zaenker
Journal: Journal of Clinical Oncology (2022)

9536 Background: The majority of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAE). It is currently not possible to predict the development of irAEs using biomarkers. Here we evaluated the IgG autoantibodies (AAbs) profile in pre-treatment sera of cutaneous metastatic melanoma patients treated with ICIs to identify AAbs that are associated with irAEs. Methods: Clinical data of patients with metastatic melanoma treated with pembrolizumab or nivolumab monotherapy (n = 48) or combination ipilimumab and nivolumab (n = 37) was retrospectively evaluated. irAEs were graded using CTCAE v5.0. Sera from the 85 patients were evaluated for IgG AAbs using the HuProt™ microarray v4.0 covering 23,059 proteins ( &gt; 81% of the human proteome). AAb profiles were compared between groups (any irAEs vs no irAEs), using the no irAEs group as control group. Results were inputted into the Advaita Bio’s iPathwayGuide software to find significantly differentially expressed AAbs using p &lt; 0.05 and Log2FC &gt; 0.6, and identify relevant biological pathways. Results: Out of 85 patients, 60 experienced any grade irAEs, 29 of 48 (60.4%) in the PD-1 group and 31 of 37 (83.8%) in the combination group. We found 758 proteins were differentially elevated, 102 in the in the PD-1 group and 666 in the combination treatment group. A comparison of these groups identified 10 AAbs that were elevated in patients experiencing irAEs independent of ICI regimen. These targeted proteins are highly expressed in tissues that are commonly affected by irAEs. Previous studies have shown their links to autoimmune and inflammatory conditions such as dermatitis and thyroiditis. Pathway analysis shows the RIG like receptor signalling pathway, which has been associated with autoinflammatory conditions, was significantly affected in the PD-1 group (p = 0.011), but not in the combination group (p = 0.442). Other pathways involved included the NOD-like receptor, purine and D-amino acid metabolism which play a role in innate immune system and assembly of inflammasomes and maturation, pro-inflammatory cytokines and mediators that contribute to inflammatory response. Conclusions: Further analyses are being conducted to identify the correlation of irAE type and severity to specific autoantibodies which will be presented. Prospective studies are required for validation of these AAbs specificities. This approach could be used to identify patients at high risk of irAEs, for treatment monitoring to maintain an effective stimulation of the patient’s anti-cancer immune response, to determine if treatment cessation is required and prevent hospitalisation or lengthy immunosuppression to treat irAEs.
Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients with muscle-invasive bladder cancer who are cisplatin-ineligible.
Authors: Daniel P. Petrylak, Thomas W. Flaig, Nataliya Mar, Theodore Stewart Gourdin, Sandy Srinivas, Jonathan E. Rosenberg, Maria Guseva, Yao Yu, Sujata Narayanan, Christopher J. Hoimes
Journal: Journal of Clinical Oncology (2022)

4582 Background: Up to 25% of all patients (pts) diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with muscle invasive bladder cancer (MIBC). Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit previously treated locally advanced or metastatic urothelial cancer pts in phase 2 and 3 trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (ypT0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred &gt; 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing phase 2 and 3 programs evaluating EV in MIBC. Clinical trial information: NCT03288545.
Personalized neoantigen DNA vaccines expand tumor-specific T cells in the periphery which infiltrate the tumor in hepatocellular carcinoma.
Authors: Renzo Perales, Mark Yarchoan, Neil Cooch, Niranjan Sardesai, Alfredo Perales-Puchalt
Journal: Journal of Clinical Oncology (2022)

2638 Background: Tumor neoantigens are epitopes derived from tumor-specific mutations that can be incorporated in personalized vaccines to prime T cell responses. DNA vaccines delivered with electroporation have recently shown strong CD8 and CD4 T cell responses in clinical trials. In preclinical studies, DNA-encoded neoantigen vaccines have shown induction of CD8 T cells against 50% of predicted high affinity epitopes with the ability to impact tumor growth. Methods: Paired blood and tumor biopsy samples were collected from a patient with hepatocellular carcinoma before and after treatment with GNOS-PV02 (DNA neoantigen targeted vaccine) + plasmid IL-12 + pembrolizumab. Treatment resulted in a partial response with a decrease in tumor size of 44% by RECIST (168 mm to 94 mm). TCRbeta sequencing was performed on all 4 samples and single cell TCR and transcriptome sequencing was performed from T cells isolated from the post-treatment blood sample. Newly identified TCRs in blood and tumor after vaccination were inserted into an expression vector and used to generate engineered TCR T cells. Engineered TCR T cells were tested against the neoantigens included in the vaccine and their responses characterized by flow cytometry. Results: We identified 67,893 new clones in PBMC after vaccination, 3 of which comprised between 0.1 to 1% of the total T cell clones. Moreover, we identified 5126 new clones in the tumor post vaccination, out of these, 3878 (75.68%) were not found within the patient’s pre vaccination PBMCs and 556 (10.86%) were identified within the pre vaccination PBMC pool. Importantly, of the newly identified T cells infiltrating the tumor post vaccination, we observed high frequency TCR clones of which 44 and 7 clones were above 0.1% and 1%, respectively. The majority of the newly identified T cell clones were CD8 T cells (68.75%) with an activated phenotype. Importantly, the 6 most expanded clones in blood were identified to be activated CD8+CD69+ T cells (81.82%). Engineered TCR T cells generated encoding the TCRs of these newly identified CD8 T cells showed activation when exposed to the tumor neoantigens encoded in the neoantigen DNA vaccine GNOS-PV02. Conclusions: GNOS-PV02, a neoantigen DNA vaccine, in combination with plasmid IL-12 and pembrolizumab resulted in expansion of newly identified T cells, primarily activated CD8, which trafficked to the tumor. These new tumor infiltrating T cells showed TCR specificity against tumor neoantigens encoded in GNOS-PV02 and may account for the observed objective decrease in tumor size.
Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, PD-1/PD-L1, and TIM-3 are markedly increased in basal cell carcinoma.
Authors: Bernardo Leon Rapoport, Nonkululeko Malinga, Shalete Siwele, Helen C. Steel, Luyanda LI Kwofie, Pieter Meyer, Teresa Smit, Ronald Anderson, Mahlatse Kgokolo
Journal: Journal of Clinical Oncology (2022)

3043 Background: Although co-inhibitory immune checkpoint proteins are primarily involved in promoting inhibitory cell-cell interactions in adaptive immunity, especially tumor immunity, the soluble cell-free variants of these molecules are also detectable in the circulation of cancer patients where they retain immunosuppressive activity. Nevertheless, little is known about the systemic levels of these soluble co-inhibitory immune checkpoints in patients with various subtypes of basal cell carcinoma (BCC), which is the most invasive and treatment-resistant type of this most commonly occurring malignancy. Methods: In the current study, we have measured the systemic concentrations of five prominent co-inhibitory immune checkpoints, namely CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3, as well as those of C-reactive protein (CRP) and vitamin D (VD), in a cohort of patients (n = 40) with BCC, relative to those of a group of control participants (n = 20), using the combination of multiplex bead array, laser nephelometry and ELISA technologies, respectively. Results: The median systemic concentrations of CRP and VD were comparable between the two groups; however, those of all five immune checkpoints were significantly elevated ( P= 0.0184 - P£0.00001), with those of CTLA-4 and PD-1 being highly correlated (r = 0.87; P&lt; 0.00001). Conclusions: This seemingly novel finding not only identifies the existence of significant systemic immunosuppression in BCC, but also underscores the therapeutic promise of immune checkpoint targeted therapy, as well as the potential of these proteins to serve as prognostic/predictive biomarkers in BCC.
Effect of primary tumor sidedness on the association of tumor-infiltrating lymphocytes with survival of patients with stage III colon cancer (NCCTG N0147) [alliance].
Authors: Bahar Saberzadeh Ardestani, Nathan R. Foster, Hee Eun Lee, Qian Shi, Steven R Alberts, Thomas C. Smyrk, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2022)

3525 Background: Tumor-infiltrating lymphocytes (TILs) are significantly associated with clinical outcomes in patients with colon cancer. However, the potential for a differential effect of TILs on prognosis based on primary tumor sidedness has not been studied. We determined the interaction between TILs and tumor sidedness in relationship to disease-free survival (DFS). Methods: We analyzed data on TIL densities by primary tumor sidedness in 1532 stage III colon carcinomas from participants in a phase III trial of FOLFOX-based adjuvant chemotherapy (NCCTG N0147). TIL densities were dichotomized as low or high (≤3 /HPF) based on an optimized cutoff previously identified for DFS in this cohort. Right-sided tumors were defined as proximal to the splenic flexure. Analysis of TILs and sidedness with DFS were examined using Kaplan-Meier methodology and multivariable Cox regression. Results: Overall, tumors with high vs low TILs had the best DFS [HR adj : 0.58 (95%CI: 0.45-0.74); P adj &lt;0.0001]. The association of TIL densities with 5-yr DFS differed significantly by primary tumor sidedness ( P interaction (adj) = 0.045). Among right-sided tumors, high vs low TILs were significantly associated with improved DFS ( P adj &lt;0.0001)[Table]. Among left-sided tumors, however, DFS did not differ significantly for high vs low TILs ( P adj =0.173)[Table]. Similar results for TILs and DFS by sidedness were found for pMMR cancers. We then analyzed our data in low risk (T 1-3 , N 1 ) and high risk (T 4 and/or N 2 ) tumors. Among low risk tumors, high vs low TILs was significantly associated with improved 5-yr DFS only in right-sided tumors ( P adj =0.006) [Table]. Among high risk tumors, high vs low TILs were significantly associated with better DFS in both right-sided ( P adj &lt;0.001) and left-sided ( P adj =0.024) tumors. Conclusions: Overall, tumors with high TIL densities had significantly better DFS in right-sided but not left-sided cancers. Among low risk patients, the association of high TILs with better DFS was limited to right-sided tumors. These findings suggest that TILs should be interpreted by sidedness for prognostication. ClinicalTrials.gov Identifier: NCT00079274 . [Table: see text]
The use of a transient transfected expression system to deliver high quality bispecific T-cell engager drug product, NVG-111, to the clinic for a fraction of the cost and time associated with the development and use of a producer cell line.
Authors: Kieran O'Donovan, Shivam Bhatt, Annalisa Baccaro, Dinusha Fernando, Angel Smith, Ephraim Gbajumo, Tomasz Bobrzynski, Jenny McIntosh, Jasmine Gore, Amit C. Nathwani, Kerry Chester, David Granger
Journal: Journal of Clinical Oncology (2022)

e14506 Background: Bispecific antibodies provide an opportunity to treat a diverse range of disorders because of their ability to simultaneously attenuate several different pathways precisely and effectively, thus overcoming many of the limitations of monoclonal antibodies. The adaptability of bispecifics has facilitated the generation of compelling preclinical data covering a range of malignant and non-malignant disorders. Proof-of-concept early phase clinical trials with bispecific antibodies, including bispecific T-cell engagers (TCE) have been hindered by manufacturing challenges, including a heavy burden in terms of time, quality and costs associated with generating a stable producer cell line. We took a more agile approach, using transient transfection to manufacture a ROR1×CD3 bispecific TCE drug product (DP [NVG-111]) for a first in human, Phase I/II clinical trial. Methods: A HEK293T cell line was expanded into 10-layer cell factories. The cells were transfected with a ROR1xCD3 scFv bispecific antibody (NVG-111) plasmid and incubated. Post incubation, the supernatant containing NVG-111 was clarified by filtration and subjected to solvent/detergent viral inactivation. This was followed by a concentration/buffer exchange step and subsequent DNA reduction using an endonuclease. NVG-111 was captured using a bind/elute Protein A column and the eluate polished on a multimodal anion exchange column in flow through mode to remove residual impurities. The eluate was formulated and concentrated to the target protein concentration, viral and sterile filtered and QC tested. The bulk drug substance was 0.2 µm filtered into Din 2R vials and the DP stored at ≤-65°C pending release. Results: The transient transfection approach resulted in the rapid tech transfer and GMP manufacture of clinical NVG-111 DP. Two batches of DP were manufactured producing 1,971 vials of NVG-111, sufficient to support the Phase I/II clinical trial in patients with advanced Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma (Clinical Trial.gov NCT04763083). Both batches met the approved specifications for identity, potency, purity/impurities, strength and safety. The exercise took less than 7 months from contract signature to DP in the freezer and cost ̃50% of the more traditional producer cell line approach. Conclusions: We established a novel GMP process in 7 months, using transient transfection to manufacture NVG-111 for Phase I/II trials. The process costed less than the more conventional manufacturing approach of using a producer cell line. The strategy offers a rapid, and very efficient way of reaching a first in human study without a trade-off between time, quality and cost.
The association of B7-H6 expression to the immune microenvironment in gastric cancer.
Authors: Jian Chen, Deqin Li, Dengjun Sun, Shujie Song, Weiwei Zhang, Ningning Luo, Minghui Ge, Mengmeng Li, Yingxue Qi, Xiaofeng Zhu, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

4025 Background: B7-H6, also known as NCR3LG1, is a promising molecule in B7 family and a ligand of natural killer (NK) -cell-activating receptor NKp30. B7-H6 can bind NKp30 and induce NK activation and cytokine secretion to exert anti-tumor effects. Studies have reported that the B7-H6 expression is significantly correlated with post-operative prognosis and distant metastasis status in patients with cancer. In patients with gastric cancer, B7-H6 high expression is significantly associated with longer OS. However, the effects of B7-H6 on immunotherapy and immune microenvironment are unknown. Herein, we used the data from TCGA database of gastric cancer to analyze the influence of B7-H6 expression on immune microenvironment. Methods: The gene expression profile and clinical data in gastric cancer were extracted from TCGA database ( http://cancergenome.nih.gov ). According to the previous reported article, 15 was chosen as the cutoff value for the expression of B7-H6, and the expression of B7-H6 is divided into two groups, high group (B7-H6 expression＞15) and low group (B7-H6 expression≤15). Kaplan-Meier analysis was used to verify the influence of B7-H6 expression on OS prognosis. “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts” (CIBERSORT) algorithm was used to analyze the proportion of immune-related cells in the two groups. “Estimation of STromal and Immune cells in Malignant Tumours using Expression data” (ESTIMATE) algorithm was used to analyze stromal and immune scores in the two groups. The differences of immune-related signatures between the two groups were calculated according to previous reports. Results: Kaplan-Meier survival analysis showed that high group was significantly associated with longer overall survival (p value = 0.016), which was consistent with previous reports. The result of CIBERSORT algorithm showed that the proportion of activation immune correlation CD8(+) T cells and NK active cells was significantly higher in low group than in high group (p＜0.05). Meanwhile, the proportion of immune suppressive correlation CD4 resting memory T cell was significantly lower in low group than in high group (p＜0.05). The result of ESTIMATE algorithm showed that the stromal score, immune score, and ESTIMATE score in low group were significantly higher than in high group (p＜0.01). The immune-related signatures, including immune signature, expanded immune signature, TLS signature, myeloid cell chemotaxis, tertiary lymphoid structure, were significantly higher in low group than in high group (p＜0.05). Conclusions: The low B7-H6 expression was correlated with better immune microenvironment. The effect of B7-H6 expression on immunotherapy needs to be further explored.
Prediction of response to neoadjuvant therapy (NAT) in early breast cancer (EBC) at community hospitals: SimBioSys TumorScope Validation Study.
Authors: John R. Pfeiffer, Karen Zwicky, Tushar Pandey, Anu K. Antony, The SimBioSys Team, John A. Cole, Clifford Wolf
Journal: Journal of Clinical Oncology (2022)

598 Background: While most cancer patients are treated at community hospitals, specialized equipment, diagnostic tests, and therapeutic regimens are generally validated at academic settings. Here we present a novel approach to precision medicine to improve outcomes in breast cancer care in the community setting. TumorScope (TS) is a biophysical modelling platform that uses only pretreatment standard of care (SoC) diagnostic data (demographics, drug regimen, imaging (DCE MRI) &amp; pathology) to construct a 3D model of the tumor. TS integrates models for tumor morphology, metabolism, vascularity, and drug behavior and simulates predicted tumor response longitudinally to NAT. With this information TS predicts the reduction in tumor volume and the pathological complete response (pCR), a surrogate marker of long-term outcome, to anticipated NAT in EBC. Methods: We performed a single center validation study to show the clinical applicability of TS. Patients at Northwest Community Healthcare that received NAT with corresponding pretreatment MRI were identified in a chart review. A validation set, independent from the training set, was generated from this list and data processed through TS (n=50). Pretreatment patient SoC diagnostic data was loaded into TS. TS predicted the weekly volumetric response throughout the treatment, and it simulated residual volume to predict pCR. The validation was performed using ground truth from post treatment assessment of pCR, radiographic volumes extracted from MRIs. Results: TS predicted pCR, prospectively defined as a simulated residual tumor volume &lt;0.01 cm 3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. TS tumor volume prediction accuracy had an area under the curve (AUC)=0.947 with sensitivity and specificity of 93.3% and 94.3% respectively. Performance was robust across all subtypes (See Table 1). TS predicted the reduction in tumor volume with a median absolute volumetric error of 3.4% as compared to radiographic volume from pre-surgery MRIs (n=50). Conclusions: In summary, TS accurately predicts patient-specific tumor volume reduction and pCR prior to NAT in EBC using only SoC pretreatment data, which could lead to a more personalized cancer care for the patient. Moreover, we demonstrate the feasibility of implementing TS at community hospitals. [Table: see text]